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Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma

I Mohiuddin1, X Cao, B Fang

  • 1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer Gene Therapy
|September 26, 2001
PubMed

Insights

Sodium butyrate enhances cancer cell death when combined with pro-apoptotic gene therapy (PAGT) in mesothelioma. This combination therapy, by decreasing anti-apoptotic proteins, shows promise for clinical application.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • The balance between pro-apoptotic (PAP) and anti-apoptotic (AAP) BCL-2 proteins is crucial for regulating apoptosis.
  • Mesothelioma is a challenging cancer where novel therapeutic strategies are needed.

Purpose of the Study:

  • To investigate if sodium butyrate (SB) inhibition of anti-apoptotic BCL-xL can enhance apoptosis in mesothelioma cells when combined with adenoviral pro-apoptotic gene therapy (PAGT).
  • To evaluate if this combination therapy increases PAP and decreases AAP, leading to augmented cell death.

Main Methods:

  • Human mesothelioma cell lines were treated with adenoviral vectors expressing Bax, Bak, or p53 (AdBax, AdBak, Adp53) and SB, alone and in combination.
  • Apoptosis and cell death were assessed using morphology, FACS analysis, and isobologram analysis for synergistic effects.

Main Results:

  • PAGT/SB combinations significantly augmented cellular death and apoptosis compared to monotherapy.
  • AdBax/SB and AdBak/SB treatments decreased AAP BCL-xL while increasing PAP Bax and Bak.
  • Isobologram analysis indicated additive or synergistic cell killing for AdBax/SB and AdBak/SB combinations.
  • SB did not significantly enhance cell killing or apoptosis when combined with Adp53.

Conclusions:

  • Combination therapy involving PAGT and SB is more effective than monotherapy in inducing apoptotic cell death in mesothelioma.
  • The synergistic effect is likely due to SB's ability to decrease BCL-xL, complementing the increased PAP induced by PAGT.
  • Therapeutic strategies combining agents that down-regulate AAP with PAGT may offer clinical benefits for mesothelioma treatment.

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